iTolerance Inc., a San Mateo, California-based biotech company, has signed an exclusive license and intends to develop the therapy toward clinical use. The technology was co-invented at UofL and at the Georgia Institute of Technology with support from the National Institutes of Health and , which funds Type 1 diabetes (T1D) research.

“Our goal is to help people with Type 1 diabetes, so they don’t have to suffer the side effects that come with immunosuppressants,” said Haval Shirwan, inventor and gratis professor in the UofL Department of Microbiology and Immunology.

In Type 1 diabetes, a condition affecting some 1.6 million Americans, the body’s immune system attacks cells in the pancreas that produce insulin, a hormone that regulates blood sugar. As a result, patients that receive pancreatic islet transplants need to be placed on immunosuppressants and cope with the possible side effects, including loss of appetite, nausea and increased risk of infection.

The technology works by training the immune system to accept insulin-producing cells through transplanted islets — cells taken from the pancreas. The islets are laced with a recombinant protein pioneered by Shirwan and Esma S. Yolcu, a gratis faculty member at UofL, known as Fas ligand (FasL), which “teaches” the immune system to see new graft as beneficial rather than a threat.

Once the immune system has been re-trained, the idea is to transplant healthy islet cells so the patient again can produce insulin on their own.

The UofL scientists teamed up with researchers at Georgia Tech to generate a to the graft site to ward off rejection. The technology has the potential to be an “off-the-shelf” treatment, and the hydrogels which hold the islets can be prepared up to two weeks ahead of the transplant. The islets also don’t need to be modified for the individual patient.

“We look forward to leveraging the technology to locally and durably induce immune tolerance of organ transplants,” said Cameron Gray, founder and chairman of iTolerance. “We believe the technology has potentially far-ranging implications for engraftment.”

iTolerance holds an exclusive license to the technology through Georgia Tech and the��, which works with startups and industry to commercialize university-born technologies.

Joule’s son lives with type 1 diabetes.

To honor her late father and help improve the lives of those with type 1 diabetes, Joule has given $500,000 to the University of Louisville Foundation to establish the William Marvin Petty, MD, Research Fund. The fund is designated to support type 1 diabetes research at the UofL School of Medicine.

“I saw the toll diabetes took on my dad, and now my son is faced with the same disease,” Joule said. “I was��not happy that medical research has not come up with anything new in the 40 years my son has been suffering. I am putting my assets behind the UofL research team.”��

That research team includes Haval Shirwan, PhD, and Esma Yolcu, PhD, of the UofL Department of Microbiology and Immunology, who are working to develop techniques to prevent and treat type 1 diabetes with particular focus on transplantation of islet cells.

Type 1 diabetes is a chronic autoimmune disease in which the pancreas does not produce enough insulin, a hormone required to convert glucose to energy in the body. There is no cure for type 1 diabetes, and standard treatment involves regular injections of insulin, which is far from keeping blood sugar in balance.

Insulin is produced in the pancreas by a type of cells called islet cells. Individuals with type 1 diabetes have too few or altogether lack the type of islet cells that produce insulin to keep glucose at the proper level. In recent years, physicians have developed a treatment in which they transplant the needed islet cells into a patient. However, the patient’s immune system often rejects the transplanted islet cells over time, attacking and killing them. To keep the transplanted cells alive, patients must take immunosuppression medications, which have a number of undesirable side effects.

At UofL, Shirwan and Yolcu have pioneered a process to create a manufactured protein known as Fas ligand (FasL), to protect the islet cells from destruction by the patient’s immune system. This process, patented by the UofL Office of Technology Transfer, is called ProtEx^��technology. ProtEx is used to create FasL, which is then applied to islet cells to protect them from destruction by the immune system once they are transplanted into the patient.

Preclinical research has shown that FasL is highly effective in protecting islet cells in small animal models. However, additional testing is necessary before the therapy can be used in humans.

“Ms. Joule’s contribution will enable us to achieve an important milestone for further development of the technology towards clinical translation by performing efficacy and safety studies. We are very grateful for that support,” Shirwan said.

Greg Postel, MD, executive vice president for health affairs at UofL, said the university is grateful for the contribution to research by and in honor of members of the Louisville community.

“We are extremely pleased that Ms. Joule has elected to support this very promising research at the University of Louisville,” Postel said “We believe her donation will allow this research to improve the lives of type 1 diabetic patients sooner rather than later.”

The technique, reported this week in the journal Nature Materials, uses synthetic hydrogel particles (microgels) to present a protein known as the Fas ligand (FasL) to immune system T-effector cells along with the pancreatic islets being transplanted. The FasL protein “educates” the effector cells – which serve as immune system watchdogs – causing them to accept the graft without rejection for at least 200 days in an animal model.

The FasL-presenting particles are simply mixed with the living islets before being transplanted into the mice, which suffer from chemically-induced diabetes. The researchers believe the FasL-presenting hydrogels would not need to be personalized, potentially allowing an “off-the-shelf” therapy for the transplanted islets.

Researchers from the University of Louisville, Georgia Institute of Technology and the University of Michigan collaborated on the work, which was supported by the Juvenile Diabetes Research Foundation and the National Institutes of Health.

“We have been able to demonstrate that we can create a biomaterial that interrupts the body’s desire to reject the transplant, while not requiring the recipient to remain on continuous standard immunosuppression,” said , the Dr. Michael and Joan Hamilton Endowed Chair in Autoimmune Disease at the University of Louisville School of Medicine and director of the Molecular Immunomodulation Program at the Institute for Cellular Therapeutics at UofL.

“We anticipate that further study will demonstrate potential use for many transplant types, including bone marrow and solid organs,” he said.

In the United States, some 1.25 million persons have type 1 diabetes, which is different from the more common type 2 diabetes. Type 1 diabetes is caused by immune system destruction of the pancreatic islet cells that produce insulin in response to glucose levels. Current treatment involves frequent injection of insulin to replace what the islets no longer produce. There is no long-term cure for the disease, though persons with type 1 diabetes have been treated experimentally with islet cell transplants – which almost always fail after a few years even with strong suppression of the immune system.

“Drugs that allow the transplantation of the islet cells are toxic to them,” said Andrés García, the Rae S. and Frank H. Neely Chair and Regents’ Professor in Georgia Tech’s George W. Woodruff School of Mechanical Engineering. “Clinical trials with transplantation of islets showed effectiveness, but after a few years, the grafts were rejected. There is a lot of hope for this treatment, but we just can’t get consistent improvement.”

Among the problems, García said, is toxicity to the islet cells from the immune system suppression, which also makes patients more susceptible to other adverse effects such as infections and tumors. Other researchers are exploring techniques to protect the islets from attack, but have so far not been successful.

The research reported in Nature Materials takes a totally different approach. By presenting the FasL protein – which is a central regulator of immune system cells – the researchers can prevent the immune system from attacking the cells. Once they are educated at the time of transplantation, the cells appear to retain their acceptance of the transplanted islet cells long after the FasL has disappeared.

“At the time of transplantation, we take the islets that are harvested from cadavers and simply mix them with our particles in the operating room and deliver them to the animal,” García explained. “We do not have to modify the islets or suppress the immune system. After treatment, the animals can function normally and are cured from the diabetes while retaining their full immune system operation.”

The hydrogels can be prepared up to two weeks ahead of the transplant, and can be used with any islet cells. “The key technical advance is the ability to make this material that induces immune acceptance that can simply be mixed with the islets and delivered. We can make the biomaterial in our lab and ship them to where the transplantation will be done, potentially making it an off-the-shelf therapeutic.”

In the experimental mice, the islets were implanted into the kidneys and into an abdominal fat pad. If the treatment is ultimately used in humans, the islets and biomaterial would likely be placed laparoscopically into the omentum, a tissue with significant vasculature that is similar to the fat pad in mice. Garcia’s lab has previously shown that it can stimulate blood vessel growth into islet cells transplanted into this tissue in mice.

In future work, the researchers want to see if the graft acceptance can be retained in more complex immune systems, and for longer periods of time. By reducing damage to the cadaver islets, the new technique may be able to expand the number of patients that can treated with available donor cells.

García’s lab uses polymer hydrogel particles that are about 150 microns in diameter, about the same size as the islet cells. They engineer the particles to capture the FasL – a novel recombinant protein developed by Shirwan and Esma S. Yolcu, associate professor of microbiology and immunology at the University of Louisville – on the particle surface, where it can be seen by the effector cells.